Alkenyl esters of 2(lower alkyl)-3-(lower alkyl)-4-acyl 3-or-4 cyclohexencarbinols

ABSTRACT

Compounds of the general formula ARE DISCLOSED WHEREIN -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; -R&#39;&#39; is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in the alkyl portion, adamantyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R&#39;&#39;&#39;&#39; and R&#39;&#39;&#39;&#39;&#39;&#39; are selected from the group consisting of lower alkyl of up to three carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.

United States Patent 91 Karmas 1 March 6, 1973 [75] Inventor:

[73] Assignee: Ortho Pharmaceutical Corporation Raritan, NJ.

George Karmas, Bound Brook, N1

[22] Filed: Sept. 14, 1970 [21] App]. No.: 72,181

Related US. Application Data [62] Division of Ser. No. 728,900, May 14, 1968, Pat. No.

[52] US. Cl .260/410.5, 260/404, 260/486 R [51] Int. Cl. ..Ct) 7c 69/52, C0 7c 33/06 [58] Field of Search ..260/410.5, 486 R, 48 8 CD, 260/488 R [56] References Cited OTHER PUBLICATIONS Chemical Abstracts, Vol. 40, 2117 (1946).

Primary Examiner-Lewis Gotts Assistant ExaminerDiana G. Rivers Attorney-Nicholas A. Gallo, III et al.

[57] ABSTRACT Compounds of the general formula are disclosed wherein R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; R is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in the alkyl portion, adamantyl, pyridyl, fury], lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to three carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.

3 Claims, No Drawings ALKENYL ESTERS F 2 (LOWER ALKYL)-3- (LOWER ALKYL)-4-ACYL 3-OR-4 CYCLOHEXENCARBINOLS This is a division of application Ser. No. 728,900, filed May 14, 1968 now US. Pat. No. 3,557,129.

The present invention relates to compounds of the general formula wherein R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; R is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to three carbon atoms in the alkyl portion, adamantyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to three carbon atoms.

The compounds of the present invention are related to the compounds disclosed in U.S. Pat. No. 3,344,147 and in my copending patent application, Ser. No. 662,310 now U.S. Pat. No. 3,591,624; 662,311 now abandoned; 662,295 now U.S. Pat. No. 3,567,770; and 560,1 16 now abandoned. The compounds of the patent and of my copending patent applications are known to possess activity as agents for the suppression of reproduction when fed orally to animals. The compounds of the present invention are active as suppres- In addition, the compounds may be prepared by the mono-acetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction scheme:

3, omorr R!!! II The following examples illustrate the preparation of some of the compounds of the invention. While only one method of preparation is disclosed for each compound, it is to be understood that any of the other methods noted above can also be utilized.

ALKYL ESTERS 1. R Hydrogen or Lower Alkyl The starting material for Examples I through V1 is (2- methyl-3-ethyl-4-phenyl-4- or 3-cyclohexenyl-l)- methanol which is suitably prepared as described in US. Pat. No. 3,344,147.

EXAMPLE I (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1 )methyl Acetate A mixture of 0.35 g of (Z-Methyl-3-ethyl-4-phenyl-3- cyclohexenyl-l )methanol and 50 mg of p-toluene-sulfonic acid in 10 ml of acetic acid is refluxed for 15 minutes and then diluted with water and extracted with hexane. The hexane solution is washed twice with dilute potassium carbonate, dried and evaporated. The oily residue is distilled to afford 0.30 g of the acetate, a colorless oil which boils at -90 C at 0.001 mm.

Calcd. for C l-l O, C, 79.37 H, 8.88

Found C, 79.14 H, 8.64

A A max: 5.75, 8.09, 9.71, 13.17, 14.26 p. (neat) EXAMPLE ll (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-l )methyl Caproate A solution of 4 g of the A-cyclohexenylcarbinol in 15 ml of dry pyridine is stirred at 0-5 C while 1 k molecular equivalents of caproyl chloride is added. The resulting pasty mixture is stirred at 25 C for 15 minutes, heated at -95 C for 15 minutes, and then cooled. Five ml of water is added and the mixture stirred vigorously for 2 hours. After dilution with ml of ether, the ether phase is washed twice with cold 5 percent hydrochloric acid to remove pyridine, and then twice with cold 5 percent sodium hydroxide. The ether solution is then dried and evaporated. The residual oil is developed on a column of alumina (neutral, W-l) prepared in benzene-hexane. Elution with benzene and ether affords the ester free of alcohol and carboxylic acid. The oily ester is distilled under high vacuum to af- R R on @i :j' CHZOH @Gcmocorv Q I l EXAMPLE III (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Octanoate This compound is prepared following the procedure of Example 11 and using octanoyl chloride. The compound is an oil which boils at ll55 C at 0.001

Calcd. for C H O C, 80.85 ;H, 10.18

Found C, 80.66 H, 10.28 AA max: 5.74, 8.56, 9.01, 11.79, 13.14, 14.25 p. (neat) EXAMPLE lV (2-Methy1-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Eicosanoate Using eicosanoyl chloride and again following the procedure of Example 11 and recrystallizing the crude solid ester from hexane (2-Methyl-3-ethy1-4-phenyl-4- cyc1ohexenyl-1 )-methyl Eicosanoate is prepared in the form of white flakes having a melting point of 4748 C Calcd. for C H O C, 82.38 H, 11.52

Found C, 82.25 ;H, 11.38 A A max. 5.74, 8.62, 11.88, 13.21 13.90, 14.22 p. (KBr) EXAMPLE V (2-Methyl-3-ethy1-4-phenyl-4-cyclohexenyl-l )methyl 2-Ethylhexanoate A mixture of 2.0 g of (2-Methyl-3-ethyl-4-phenyl-4- cyclohexenyl-l)methanol and 6.3 ml of a 20 percent solution of butylethyl ketene in toluene is held for one hour at 25 C and then for 1 hour at 100 C. After the addition of methanol to destroy excess ketene, the toluene solution is evaporated and the oily residue is chromatographed on alumina (benzene-hexane elution) to isolate the crude ester. The ester is then further purified by two distillations to yield 1.7 g of a colorless mobile oil which boils at 150154 C at 0.001 mm.

Calcd. for C l-1 0 C, 81.76 H, 10.29 Found C, 81.16 H, 10.24 A A max. 5.77, 8.52, 8.71,10.00,11.80,13.17,14.28 p. (neat) Any alkyl ester of the basic carbinol can be prepared by selecting the proper acid, acid chloride, acid anhydride or ketene. The A or A analog is prepared by utilizing the appropriate carbinol.

EXAMPLE V1 (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Benzoate This compound is prepared using benzoyl chloride in the procedure of Example 11. It is a colorless viscous oil which boils at 180-l C at 0.001 mm.

Calcd. for C H O C, 82.59 H, 7.84

10 (m-tolyl)-4-cyc1ohexenyl-l ]methanol Found C, 82.38 H, 7.71 A A max: 5.81, 7.85, 9.00, 9.32, 9.72, 11.81, 13.18, 14.0 (neat) EXAMPLE V11 [2-Methyl-3-ethy1-4-(m-to1yl)-4-cyclohexenyl 1 ]methyl Octanoate This compound is formed from [2-Methyl-3-ethyl-4- and octanoyl chloride following the procedure of Example 11. The carbinol starting material is prepared in the manner described in my copending application Ser. No. 662,311.

The compound is a pale yellow oil which boils at 155-l 65 C at 0.001mm.

Calcd. for C -H 0 C, 81.03 ;H, 10.34 Found C, 81.05 ;H, 10.36

AA max: 5.77, 8.58, 9.03, 11.81, 12.83 14.19 a

(neat) Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example II from the ap- 2 propriate carbinol. The ortho and para analogs also may be prepared following this same procedure. The

starting carbinols for the latter are prepared as described in the above-noted copending application and my copending application Ser. No. 662,310.

2. R Lower Alkoxy EXAMPLE VIII [2-Methy1-3-ethyl-4-(o-anisyl)-4-cyclohexenyl- 1 ]methyl ,Hexanoate To a stirred solution of 3.1 g of 2-Methyl-3-ethyl-4- hydroxy-4-(o-anisyl) cyclohexanecarboxylic acid, (the preparation of which is disclosed in my copending application Ser. No. 662,295) in ml of tetra-hydrofuran is added cautiously 4.0 g of lithium aluminum hydride. The reaction mixture is refluxed with stirring for one hour and then hydrolyzed in a large volume of ice and water. After acidification with dilute hydrochloric acid, the mixture is filtered, the filter cake being washed well with ether and water. Organic products in the filtrate are separated by extracting twice with ether; and the combined ether solution is then washed with dilute sodium hydroxide, dried and evaporated. The ether residue is distilled to afford 3.0 g of a pale yellow glass having a boiling point of -14 5 C at 0.001 mm. This is the 1,4-diol: [2-Methyl-3- ethyl-4-hydroxy-4-(o-anisyl) cyclohexanyl- 1]methanol.

Calcd: C, 73.34 H, 9.41

Found: C, 73.20 H, 9.53 A A max: 2.92, 8.10, 9.70, 11.00, 12.51, 13.24 (KBr) A solution of 2.6 g of the 1,4-diol, discribed above, and 6 ml of hexanoic anhydride in 20 ml of pyridine is heated at 85 C for 1 lhours, 2 m1 of water added and heating continued at 85 C for one-half hour more. The solution is diluted with hexane and the hexane solution is washed with water, twice with dilute hydrochloride acid, and twice with dilute potassium carbonate. After drying and evaporation of the hexane solution, the oily residue is distilled to afford 3.0 g of a yellow oil having a boiling point of 160165 C at 0.001 mm. This is the ester-monoalcohol: [2-Methyl-3-ethyl-4-hydroxy-4-(oanisyl) cyclohexanyl-l lmethyl l-lexanoate.

Calcd: C, 73.36 H, 9.64

Found: C, 74.32 H, 9.76 A A max: 2.83, 5.78, 8.10, 8.50, 9.70, 12.51, 13.23 p. (neat) A solution of 1.0 g of the ester-monoalcohol and 4 ml of boron trifluoride etherate in ml of ether is held at 2025 C for 5 hours and then further diluted with ether and washed twice with aqueous potassium carbonate. The ether solution is dried and evaporated and the oily residue is distilled to afford 0.8 g of [Z-Methyl- 3-ethyl-4-(o-anisyl)-4-cyclohexenyl-l ]methyl l-Iexanoate, a yellow oil which boils at 140-l 45 C at 0.001

Calcd: C, 77.05 H, 9.56

Found: C, 76.86 H, 9.39

A A max: 5.75, 8.02, 8.50,11.82,13.28 p. (neat) Other esters of the o-anisyl series can be prepared by selecting the proper acid anhydride. In forming the psubstituted esters the starting carbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,1 16.

3. R I-Iydroxyl and Acyloxy EXAMPLE IX [2-Methyl-3-ethyl-4-(p-acetoxyphenyl)-4- cyclohexenyl-l ]-methyl Acetate To a stirred solution of 4.0 g of 2-Methyl-3-ethyl-4- (p-hydroxyphenyl)-4-cyc1ohexenecarboxylic acid (prepared as described in my copending application Ser. No. 560,1 16) in 250 ml of tetrahydrofuran is added cautiously 7.0 g of lithium aluminum hydride. The thick mixture is stirred at 20-25 C for 20 hours and then it is hydrolyzed in a large volume of ice and water. After the mixture has been acidified with dilute hydrochloric acid, it is filtered and the filter cake is washed thoroughly with ether and water. The organic products in the filtrate are separated by two extractions with ether and then the combined either solution is washed twice with aqueous potassium bicarbonate, dried, and evaporated to a solid residue. The latter is recrystallized from either to afford 2.5 g of white prisms which melt at 166l 67 C. This is the carbinol, [2-Methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-l lmethanol:

Calcd. for c,,u,,o, C, 78.01 ;l-l, 9.00

Found: C, 78.01 H, 9.06

A A max: 2.92, 6.61, 8.00, 8.17, 9.97, 11.76, 12.10 p. (KBr) A solution of 1.5 g of the carbinol and 7.0 ml of acetic anhydride in 20 ml of pyridine is heated at 70 C for one-half hour and then it is hydrolyzed in ice plus water. The hydrolysis mixture is extracted twice with ether and the combined ether solution is washed twice with dilute hydrochloric acid and then with aqueous potassium bicarbonate. After drying and evaporation of the ether solution, the oily residue is distilled to afford 1.6 g of [2-Methyl-3-ethyl-4-(p acetoxyphenyl)-4- cyclohexenyl-l l-methyl Acetate, a colorless oil which boils at l35140 C at 0.001 mm.

Calcd. for C H O C, 72.70 H, 7.93

Found C, 72.44 H, 8.00 A A max: 5.68, 5.74, 7.30, 8.33, 9.68, 9.80, 10.97, 11.83 p. (neat) Other di-esters of the para-hydroxy phenyl carbinols may be prepared by selecting the proper acid chloride.

EXAMPLE X [2Methyl-3-ethyl-4-(p-hydroxyphenyl)-4- cyclohexenyl-l l-methyl Acetate This and other hydroxy derivatives are obtained from the appropriate di-esters which are in turn prepared as described in Example IX.

A mixture of 1.0 g of the diacetate, 0.8 g of potassium bicarbonate, 10 ml of water, and 17 ml of methanol is refluxed for five minutes and then diluted with cold water. The organic material is extracted with an etherhexane mixture which is dried and evaporated to an oily residue which slowly crystallizes. This crude monoacetate is recrystallized from hexane containing 5 percent ether to afford 0.5 g of [2-Methyl-3-ethyl-4'(phydroxy-phenyl)-4-cyclohexenyl-l ]methyl Acetate in the form of white prisms which melt at 6772 C.

Calcd. for C H O C, 74.97 ;H, 8.39

Found C, 75.74 H, 8.68 A A max: 2.89, 5.81, 6.61, 7.90, 9.68,11.76, 11.91 p. (KBr) EXAMPLE XI [2-Methyl-3-ethyl-4-(p-isobutyryloxyphenyl)-4- cyclohexenyl-l ]-methyl Acetate Where the acyloxy group is different from the ester group, the compound is produced from the p-hydroxyphenyl mono ester obtained as described in Example A solution of 0.35 g of the phenolic monoacetate and 2.5 ml of isobutyric anhydride in 15 ml of pyridine is held at 25 C for 3 hours and then hydrolyzed by stirring with water for 1 hour. The product is extracted with hexane and the hexane solution is washed with dilute hydrochloric acid and with potassium carbonate. After drying and evaporation of the hexane solution, the residue is distilled to afford 0.35 g of [2-Methyl-3- ethyl-4-(p-isobutyryloxyphenyl)-4-cyclohexenyl-1 ]methyl Acetate, a colorless oil which boils at l45l 5 0 C at 0.001 mm.

Calcd. for C l-1 0 C, 73.71 ;I-I, 8.44

Found C, 73.58 H, 8.48 A A max: 5.70, 5.75, 8.10, 8.31, 8.57, 8.81, 9.69, 10.90, 11.48, 11.80 p. (neat) 4. R Anilino EXAMPLE XII [2-Methyl-3-ethy1-4-(p-dimethylanilino)-3 and 4- cyclohexenyl-l ]-methyl Valerate This compound is prepared from 2-Methyl-3-ethyl-4- (p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acid which is prepared as described in my copending patent application Ser. No. 662,31 1.

To a stirred solution of 3.0 g of the inseparable mixture of 2-Methyl-3-ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acids in ml of tetrahydrofuran is added cautiously 3.0 g of lithium aluminum hydride. The mixture is stirred at 25 C for 20 hours and then it is hydrolyzed in a large volume of ice and water. This hydrolysis mixture is filtered and the filter cake is washed thoroughly with ether. The product is isolated by two extractions of the filtrate with ether and the combined ether solution is dried and evaporated. The oily ether residue is distilled to afford 2.5 g of a very viscous yellow oil which boils at 140-14 C at 0.001 mm. This is the carbinol mixture, [2- Methy1--ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenyl-l ]-methanol:

Calcd. for C H ON C, 79.07 H, 9.95

Found:C,79.08 ;H,9.9l

AA max: 2.99, 6.20, 6.59, 7.40, 9.42, 9.70, 9.91, 10.58,12.29 p. (neat) A solution of 1.0 g of the mixed carbinol described above and ml of pyridine is stirred and cooled in an ice bath while 3 ml of valeryl chloride is added. The dark mixture is held at 20 for 3 hours and then it is hydrolyzed by stirring with water and hexane for one hour. The hexane layer is separated and is washed twice with dilute sodium hydroxide, dried, and evaporated. The oily residue is developed onto a chromatographic column of neutral alumina, and elution with ether affords the crude ester. Distillation of the ester gives the mixture of [2-Methyl-3-ethyl-4-(p-dimethylani1ino)-3 and 4-cyclohexenyl-l ]methy1 Valerate as a yellow oil which boils at 160165 C at 0.001 mm.

Calcd. for C H O N C, 77.26 H, 9.07

Found C, 77.82 H, 9.95 A A max: 5.77, 6.20, 6.59, 7.41, 8.57, 10.56, 12.28 p. (neat) Adamantoate Esters EXAMPLE XIII (2-Methyl-3-ethyl-4-phenyl-3-cyc1ohexenyl-1 )methyl l-Adamantoate This compound is prepared from (2-Methyl-3-ethy1- 4-phenyl-3-cyc1ohexenyl-1)methanol and Adamantoic acid chloride following the procedure of Example 11.

Calcd. for C H O C, 82.60 H, 9.24

Found C, 82.37 H, 9.41 A A max: 5.80, 8.07, 8.45, 9.25, 13.19, 14.28, 14.74 p. (1(Br) EXAMPLE XIV [2-Methy1-3ethyl-4-(p-anisyl)-4-cyclohexenyl- 1 ]methyl l-Adamantoate This compound is prepared from [2-Methyl-3-ethy1- 4-(p-anisyl)-4-cyc1ohexeny1-1 ]methanol and Adamantoic acid chloride following the procedure of Example 11. It is a viscous oil which boils at 200-220 C at 0.002

Calcd. for C H O C, 79.58 H, 9.06 Found C, 79.23 H. 9.09

xx max: 5.80, 8.01-8.12, 8.42, 9.02, 9.24, 9.60;

11.93, 13.50 p. (neat) Cycloalkyl Lower Alkyl Esters EXAMPLE xv [2-Methyl-3-ethyl-4-(p-anisyl)-3-cyc1ohexenyl- 1 ]methyl B-Cyclopentylpropionate This compound is formed from cyclopentylpropionic acid chloride and [Z-Methyl-3-ethy1-4-(p-anisyl)-3- cyclo-hexenyl-l methanol according to the procedure of Example 11. The compound is an oil which boils at l60170 C at 0.001 mm.

Calcd. for C ,,H O C, 78.08 H, 9.44

Found C, 78.04 H, 9.49

A A max: 5.75, 8.01, 8.49, 9.61, 12.04 p. (neat) NMR (CDCl,,) 0.73, 0.84, 0.96, 0.90, 1.01

Furoates and Nicotinates EXAMPLE XVI (2-Methyl-3-ethyl-4-phenyl-4-cyc1ohexeny1-1 )methyl Nicotinate This compound is prepared using nicotinoyl chloride following the procedure of Example 11 but ommitting the HCl washing. It is a yellow oil which boils at 175-180 C at 0.001 mm.

Calcd. for C H O N C, 78.77 ;H, 7.51

Found C, 78.54 H, 7.57 A A max: 5.79, 7.78, 8.81, 8.95, 9.73, 11.80, 13.15, 13.50, 14.27 p. (neat) EXAMPLE XVII (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-l )methyl 2-Furoate This compound is prepared generally following the procedures of Example 11 and using 2-furoyl chloride to afford white granules which melt at -72 C.

Calcd. for C l-1 0;, C, 77.75 H, 7.46

Found: C, 77.81 H, 7.54

0 A A max: 5.86, 7.70, 8.56, 9.00, 11.83, 12.92, 13.17,

14.3011. (KBr) Other Miscellaneous Esters of the Carbinols Including Esters with Dibasic Acids, Unsaturated Acids, Etc.

EXAMPLE XVIII (2-Methyl-3-ethyl-4-phenyl-4-cyc1ohexenyl-1 )methyl Hemisuccinate A solution of 3.1 g of the carbinol and 9.0 g of succinic anhydride in 60 m1 of pyridine is heated at 90-95 C for 1 hour, then 9 ml of water is added and heating is continued for 15 minutes longer. The mixture is diluted with hexane'and the hexane solution washed four times with water to remove succinic acid, dried and evaporated. Distillation of the oily residue affords 3.4 g of the hemisuccinate, a viscous colorless oil which boils at l -190 C at 0.001 mm.

Calcd. for C H Q, C, 72.70 H, 7.93

Found C, 72.61 H, 8.05 A A max: 5.77, 5.83, 8.57,10.03,11.82, 13.17, 14.28 p. (neat) EXAMPLE XIX (2-Methyl-3-ethyl-4-phenyl-4-cyc1ohexenyl- 1 )methyl Succinamate 1.0 g of the compound of Example XVIII and 8 m1 of thionyl chloride is refluxed for 20 minutes, diluted with 20 ml of toluene, and evaporated to afford an oily residue of the ester acid chloride. The latter is dissolved in 20 ml of cold dioxane and this solution is treated with 4 ml of 28 percent aqueous ammonia. After a period of 1 rhours at 20 C this reaction mixture is diluted with water and extracted with ether. The ether solution is washed with water, dried and evaporated. The residue is recrystallized from ether to afford 0.68 g of the ester amide, white prisms which melt at 909 1 C.

Calcd. for C H O N C, 72.92 H, 8.26

Found C, 72.77 H, 8.44

A11 max: 2.95, 3.11, 5.78, 5.97, 7.42, 8.49, 10.12,

11.88,13.20,14.23 p. (KBr) EXAMPLE XX (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Ethyl Succinate EXAMPLE XXI (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1 )methyl Succinate This compound is prepared utilizing succinyl chloride and following the procedure of Example 11. The product is purified by chromatography on alumina to yield a yellow oil.

Calcd. for C H O C, 79.66 H, 8.54

Found C, 80.61 H, 9.06 AA max: 5.75, 8.60, 9.96, 10.13, 13.17, 14.27 p. (neat) EXAMPLE xxn (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1 )methyl IO-Undecenoate This compound is prepared using undecenoyl chloride and following the general procedure of Example II to yield a colorless oil which boils at 175-180C at 0.001 mm.

Calcd. for C H O C, 81.76 H, 10.17

Found C, 81.68 H, 10.23

AA max: 5.75, 8.52, 10.00, 11.00, 13.18, 14.27 p. (neat) While the preparation of only some of the compounds of this invention has been specifically described, one skilled in the art should be able to prepare the remainder of the compounds following the general techniques set forth.

As mentioned previously, the compounds of this invention exhibit anti-littering effects when given orally or parenterally and are estrogenic agents to varying degrees.

Estrogenic effects are measured against the estrogenic effects of estradiol as a standard. In carrying out the test, female rats of a Wistar-derived strain are bilaterally ovariectomized under light ether anesthesia. About a week following surgery all animals are given a priming dose of 2-10 14g estradiol-l 73 by subcutaneous injection and vaginal smears are taken on each of the next two days. Animals which do not shown vaginal cornification are rested a week and reprimed. Rats which respond positively to the priming injection are rested a week and then given a single subcutaneous injection of the test material in sesame oil. Vaginal smears are taken daily to assess the duration of estrogenic response (vaginal cornification) in each animal as opposed to the vaginal cornification induced by the priming. The results, tabulated in Table I, for certain of the compounds prepared according to the examples hereinbefore set out show that the compounds of this invention have substantial estrogenic activity.

The parenteral anti-littering properties of the compounds are measured by administering to adult female rats of Wistar'derived strain a single subcutaneous injection of the test material in sesame oil. Controls receive sesame oil vehicle only. Ordinarily twenty animals are assigned to each group.

Both groups are cohabitated with adult male rats in the ratio of three males per five females starting on the day of treatment. Rats are examined twice weekly for gross signs of pregnancy. Gravid animals are removed and allowed to deliver so that a count of young and their condition may be recorded. The mean interval between drug administration (and cohabitation) and conception is calculated for each group using an average gestation length of 21 days.

Cohabitation is continued for 90 days or until 80 percent of the females become pregnant, whichever occurs sooner.

The minimum dosage in mg/Kg body weight required to prevent littering in the rats for various compounds, the preparation of which was specifically described in the examples, is set out in Table I. The actual effect of some of the compounds on littering at various dosage levels is set out in Table II.

"'T'A'i'ffi 1 -CH OC--R 2 H O CZH5 CH3 Pharmacological activity Antilittering Estrogenic parenteral Example R R A (times EE) (mg,)

11 C113... 1A.. 11 (1113.. 1 2.1 -2-5 II... 11 C511"... 3 1/4 11A 11 C511 1 111...... 11 (l111|.-.. 4 1.7 1 IV 11 0,911.. l (1,51)

TABLE I -Continued -CII 10% It O C 11 CH Pharmacological activity Antilittering Estrogcnic parenteral Example R R A (times EE) hug.)

X p-Oll -CH3 4 XI p-Ofik-CIHCIIQ; CH3... 1

XII p-N(CH -C Hg 3 1: 4 v 001 V VVVVVVV XIIL. H Adamantyl-l 3 l. 2 1 XIIIA H (10 4 2/3 35 XIV p-OCH; t 4/3 1 XV p-OCII; l 3 2 21 C 11 0 Hz J XVI". lI Pyridyl-3 1 (1x0 XVII. ll Furyl-2... 4 (1.80 XlX.. ll -Cll Cll (j()Nll 4 1.4 XX1I ll '((11I1)g(111 117, 4 0.80 l

' !l0 (lnys,

'lAll LF Il Nninlmr llttvrs/ Mann vnluo (luy number rots pregnancy occurred Compound of Dose, Expcrl- Expori- Days cooxamplc lngJkg. Control mental Control mental hahltatcd II 0. 10/10 7/10 10 3 14 7 35 0. 25 15/16 4/16 1 4 8 X 15 0. 15/16 0/ 15 1. 0 22/26 0/26 15-El0 III 0.1 /10 10 10. 3 7. 3 27 1. 0 10/10 5/10 10.3 50.5 10 XV 0.1 10/10 7/10 10.3 10 0 27 0. 25 16/16 2/16 5. 4 I 0 0.5 16/16 /016 l5 XIIIA V u 0. 5 16/20 15/20 4. 7 7 .1 33-34 1. 0 16/20 16/20 4. 7 7. 1 33-62 2. 5 19/20 3/20 5. (I 15.0 00 5. 0 10/10 0/ V l5 XIII 0. 5 11/10 8/10 6). 2 0 B 27 1. 0 16/20 10/20 (i 12 7 700 2. 5 10 0/10 v V v 00 XIV 0.1 10/10 10/10 10 3 8 l 27 1.0 10/10 3/10 10 3 33 7 J0 What is claimed is: atoms, lower alkyl of up to eight carbon atoms, and

lower alkyl anilino of up to four carbon atoms; R' is alkenyl of up to carbon atoms, and R" and R' are selected from the group consisting of lower alkyl of up 11 to three carbon atoms. II

5 S 2. The compounds of claim 1 wherein R is hydrogen. wherein R is selected from the group consisting of (2'Methyl'3'ethyl'4'pljlenyl'3'cyclohexenyl'1)' hydrogen, hydroxy, lower alkoxy of up to eight carbon methyl lo'undecenoate of clam 1. Compounds of the formula 75 7 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 719,693 Dated March 6, 1973 Inventor( s) George mBS It is certified that error appears in the shove-identified patent and that said Letters Patent are hereby corrected es shown below:

GT1 Column L, line 66 "h dr hl hould read .f /droch1oric" In Column 5, line U5, "either" should read "ether" In Column 5, line &8, "either" should read "ether" In Column 7, lines 9, 8c 10 2-Methyl-Ethyl should read "2-Methyl-3-Ethyl" Signed and sealed this 9th day of April 1972+.

(SEAL) Attest:

EDWARD I-'I.I*LETCHER,JR. C. MARSHALL DAMN Attesting Officer Commissioner of Patents 

1. Compounds of the formula wherein -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to eight carbon atoms, lower alkyl of up to eight carbon atoms, and lower alkyl anilino of up to four carbon atoms; -R'' is alkenyl of up to 20 carbon atoms, and R'''' and R'''''' are selected from the group consisting of lower alkyl of up to three carbon atoms.
 2. The compounds of claim 1 wherein R is hydrogen. 